Temporomandibular disorders (TMD) have estimated annual health and societal costs of $4 billion (Stowell et al., 2007). Women are 1.5-2 times more likely to be afflicted. Temporomandibular joint (TMJ) disc dysfunctions with joint pain are found in approximately 30% of TMD patients (Schiffman et al., 2010). Osseous changes are late-stage characteristics of degenerative joint disease (DJD) (Farina et al., 2009;Wiese et al., 2008;Luder, 2002) yet generally occur more than a decade earlier in the TMJ than in other human joints. Fatigue failure of TMJ tissues could cause disc dysfunction, inflammation, pain, and osseous changes. Mechanical fatigue depends on magnitude and duty factor of energy input to tissues, plus innate susceptibility of these tissues. Our pilot work estimated magnitudes of energy densities in human TMJs and suggests that higher energy densities occur in women compared to men and in a subject group with TMJ disc displacement (DD) compared to a healthy group (Nickel et al., 2009c). To be determined are duty factor of TMJ loading behaviors, e.g. time of jaw loading out of a total given day, and innate inflammatory response and susceptibility to pain, e.g. inflammation and pain gene risk haplotypes. Therefore, our short-term working hypothesis: Differences in TMJ disc position and pain (as classified by Research Diagnostic Criteria for TMD including imaging of the TMJs) in women and men are predicted by mechanics, behavior, and extended gene haplotype, were used to derive 4 Specific Aims: Specific Aim #1: Determine if predicted energy densities within the TMJ during jaw movement are larger in women compared to men and in subjects with DD compared to healthy subjects. Specific Aim #2: Test the hypothesis that inter-group differences in mechanics result in magnitudes of compressive stresses in the TMJ that are larger in subjects with DD without joint pain, and smaller in subjects with DD and joint pain and in healthy subjects. Specific Aim #3: Determine if duty factors of behaviors which load the jaws are higher in subjects with DD and joint pain compared to subjects with DD without joint pain and to healthy subjects. Specific Aim #4: Determine if a limited 3-domain model of energy density, duty factor of loading, and extended gene haplotype predicts disc position in subjects with and without joint pain. The health-relevant outcomes of the proposed work will be groundwork mechanical, behavioral, and genetic data for therapeutic models, and foundational data for identification of healthy subjects at risk for TMD, degeneration and pain for future longitudinal studies. PUBLIC HEALTH RELEVANCE: Why degenerative disease occurs earlier in the TMJ than other human joints is unknown. Fatigue of TMJ tissues could cause disc dysfunction, inflammation, pain, and osseous changes. How mechanics, behaviors and innate traits, plus sex-bias in these variables, combine to promote premature fatigue of TMJ tissues and pain will be measured, resulting in a multidomain articular tissue model applicable to other joints (e.g. knee).